Spatially Resolved Transcriptomics Reveals Local Invasion-Related Genes in Liver Hepatocellular Carcinoma: Exploring the Therapeutic Potential of a Chimeric Protein Targeting Glypican-3

Abstract

Despite advancements in cancer therapy, hepatocellular carcinoma (HCC) remains a major health concern due to late-stage diagnosis and poor prognosis. In this study, the expression of Glypican-3 (GPC3), a cell surface protein encoded by the GPC3 gene was analyzed at both Messenger RNA and protein levels. The goal was to advance understandings into the role of GPC3 in HCC progression and design a fusion protein as a potential therapy targeting cancer cells expressing this oncogene. Expression analysis of GPC3 in liver hepatocellular carcinoma (LIHC) was performed using GEPIA 2 and OncoDB servers. The analysis revealed a significantly high expression level of GPC3 in cancerous tissues of HCC, with a p-value of p = 1.07e-37. This finding indicates the potential involvement of GPC3 in HCC development. To construct the chimeric proteins (CPs), rituximab, a linker, and an approved Anti-Ogawa O-antigen monoclonal antibody S-20-4 penetrating peptide were combined using trRosetta. The peptide sequence of the Anti-Ogawa O-antigen monoclonal antibody S-20-4, namely, NHNYPPLSLLTF, SHDWRLMLSHLQ, QHDRLLMLSYLV, HHILPPKALLFG, SHTFPPSWLLVR and YSVKPPLPYLPP was obtained from the Immunet BDB database. The HDock scoring algorithms were employed to assess the degree of connection between the CP and the GPC3 gene expressed in HCC. The analysis showed a strong binding affinity of -258.53 KJ/mol between the CP and GPC3, indicating a favorable interaction. Simulations and toxicity analysis further supported the therapeutic potential of the constructed CP for treating LIHC. These findings highlight the potential of the CP as a targeted therapy against HCC, leveraging the high expression of GPC3 in cancerous tissues.